The Intergroup Rhabdomyosarcoma Study (IRS) is designed to answer important therapeutic, clinical, and laboratory research questions about rhabdomyosarcoma. The IRS has been in existence since 1972 and is a collaborative multidisciplinary study carried out by Children's Cancer Study Group (CCSG) and the Pediatric Oncology Group (POG). Eligible patients in CCSG and POG institutions are registered on the IRS protocols. There have been three protocol studies: IRS-I (1972-78), IRS-II (1978-84), and IRS-III (1984-88, some strata are still open). The fourth protocol, IRS-IV, is in pilot phase (1987- ), and will soon begin. Between 686 and 1002 patients have been entered on each full study (IRS-I,-II,-III). Each protocol beginning with IRS-II developed as an outgrowth of the preceding study. The result of IRS-I,-II,-III have shed light on various surgical, radiotherapeutic and chemotherapeutic aspects of treatment in relation to disease stage, primary tumor site, tumor histology and patterns of disease spread. Patient survival and complete remission (CR) duration have increased progressively and significantly from IRS-I to -II to -III with incremental intensification of therapy to defined risk groups. At 3 years, the overall survival rate of 73% in IRS-III is superior to IRS-II, 67%, and IRS-I, 60% p<.001. The same relationship is true for CR duration (76% vs 69% vs 64%, p<.001). Patient follow-up and data analysis will continue until all patients have been followed for a minimum of 5 years from the start of treatment. Late treatment effects are being monitored and identified in selected patient subgroups. IRS-IV will be activated by late 1989. It will accrue patients over a 4-year period. Pilot studies of the component regimens are in progress. A new IRS-derived TNM pre-treatment staging classification will determine treatment randomization. The main chemotherapy questions are (1) comparison of the efficacy of cyclophosphamide vs ifosfamide vs ifosfamide + VP-16, and (2) rank ordering of induction drug doublets (vincristine/melphalan vs ifosfamide/etoposide vs ifosfamide doxorubicin) and their clinical cross-resistance to VAC therapy. A major radiotherapy question also will be addressed: hyperfractionated dose vs conventional dose. Other studies will include: immunohistochemistry, electron microscopy, cytogenetics, DNA flow cytometry, monoclonal antibody probes, establishment of a tumor cell bank for molecular genetic and other studies of tumor tissue, pilot studies of new therapies, late effects, and epidemiology.